rs765138678

Variant names:

• chr5-87341313-A-G
• rs765138678
• NM_002890.3:c.1041A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002890.3(RASA1):​c.1041A>G​(p.Glu347Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000264 in 1,357,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: RASA1 NM_002890.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.15
• Publications: 1 publications found

Genes affected

RASA1 (HGNC:9871): (RAS p21 protein activator 1) The protein encoded by this gene is located in the cytoplasm and is part of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Mutations also have been associated with hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM) and Parkes Weber syndrome. Alternative splicing results in two isoforms where the shorter isoform, lacking the N-terminal hydrophobic region but retaining the same activity, appears to be abundantly expressed in placental but not adult tissues. [provided by RefSeq, May 2012]

CCNH (HGNC:1594): (cyclin H) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. They participate in two different transcriptional regulation processes, suggesting an important link between basal transcription control and the cell cycle machinery. A pseudogene of this gene is found on chromosome 4. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 5-87341313-A-G is Benign according to our data. Variant chr5-87341313-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 416846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000212 (32/151288) while in subpopulation NFE AF = 0.000398 (27/67844). AF 95% confidence interval is 0.000281. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASA1	NM_002890.3	c.1041A>G	p.Glu347Glu	synonymous_variant	Exon 6 of 25	ENST00000274376.11	NP_002881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASA1	ENST00000274376.11	c.1041A>G	p.Glu347Glu	synonymous_variant	Exon 6 of 25	1	NM_002890.3	ENSP00000274376.6

Frequencies

GnomAD3 genomes AF: 0.000212 AC: 32 AN: 151170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000398

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000154 AC: 11 AN: 71636 AF XY: 0.0000749

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000271 AC: 327 AN: 1206286 Hom.: 0 Cov.: 26 AF XY: 0.000280 AC XY: 165 AN XY: 589232

African (AFR) AF: 0.0000410 AC: 1 AN: 24374

American (AMR) AF: 0.000134 AC: 2 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20056

East Asian (EAS) AF: 0.00 AC: 0 AN: 29204

South Asian (SAS) AF: 0.00 AC: 0 AN: 43026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3496

European-Non Finnish (NFE) AF: 0.000317 AC: 310 AN: 979410

Other (OTH) AF: 0.000286 AC: 14 AN: 48908

GnomAD4 genome AF: 0.000212 AC: 32 AN: 151288 Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 13 AN XY: 73942

African (AFR) AF: 0.00 AC: 0 AN: 41094

American (AMR) AF: 0.000264 AC: 4 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000398 AC: 27 AN: 67844

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000353 Hom.: 0

Bravo AF: 0.000242

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Capillary malformation-arteriovenous malformation syndrome Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Apr 03, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RASA1-related disorder Benign:1

Mar 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		7.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765138678; hg19: chr5-86637130; COSMIC: COSV57194584;